title: Effect of structural modification in the amine portion of substituted aminobutyl-benzamides as ligands for binding σ1 and σ2 receptors.
abstract: 5-Bromo-N-[4-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-butyl)]-2,3-dimethoxy-benzamide (1) is one of the most potent and selective σ(2) receptor ligands reported to date. A series of new analogs, where the amine ring fused to the aromatic ring was varied in size (5-7) and the location of the nitrogen in this ring was modified, has been synthesized and assessed for their σ(1)/σ(2) binding affinity and selectivity. The binding affinity of an open-chained variant of 1 was also evaluated. Only the five-membered ring congener of 1 displayed a higher σ(1)/σ(2) selectivity, derived from a higher σ(2) affinity and a lower σ(1) affinity. Positioning the nitrogen adjacent to the aromatic ring in the five-membered and six-membered ring congeners dramatically decreased affinity for both subtypes. Thus, location of the nitrogen within a constrained ring is confirmed to be key to the exceptional σ(2) receptor binding affinity and selectivity for this active series.
authors.affiliation: Department of Chemistry, University of Missouri-Columbia, Columbia, MO, USA.
authors.forename: Kuo-Hsien
authors.initials: KH
authors.lastname: Fan
authors.forename: John R
authors.initials: JR
authors.lastname: Lever
authors.forename: Susan Z
authors.initials: SZ
authors.lastname: Lever
mesh_terms: D000588:Amines / Q000737:chemistry*; D001549:Benzamides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D007546:Isoquinolines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D008024:Ligands; D011485:Protein Binding; D017480:Receptors, sigma / Q000378:metabolism*; D000097605:Sigma-1 Receptor
chemical_list: D000588:Amines; D001549:Benzamides; D007546:Isoquinolines; D008024:Ligands; D017480:Receptors, sigma; D000097605:Sigma-1 Receptor; C559072:5-bromo-N-(4-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)butyl)-2,3-dimethoxybenzamide; C106107:sigma-2 receptor